Indole synthesis: a review and proposed classification

Abstract

The indole alkaloids, ranging from lysergic acid to vincristine, have long inspired organic synthesis chemists. Interest in developing new methods for indole synthesis has burgeoned over the past few years. These new methods have been fragmented across the literature of organic chemistry. In this review, we present a framework for the classification of all indole syntheses. As we approach the classification of routes for the preparation of indoles, we are mindful that the subject has occupied the minds of organic chemists for more than a century. There have been many reviews of indole synthesis.1 We were also aware that much more could be said than we have written. We have only briefly covered the conversion of indolines into indoles, and the reduction of oxindoles to indoles. We have not covered the extensive literature on the modification of existing indoles. Throughout, our interest has been to be illustrative, not exhaustively inclusive. It is apparent, however, that every indole synthesis must fit one or the other of the nine strategic approaches adumbrated here. The web of scientific citations unites and organizes the world-wide research effort. It is our intention that the system put forward here for classifying indole syntheses will be universally understood. As authors conceive of new approaches to the indole nucleus, they will be able to classify their approach, and so readily discover both the history and the current state of the art with that strategy for indole construction. In addition to avoiding duplication, it is also our hope that efforts will then be directed toward the very real challenges that remain to be overcome. It is noteworthy that, in the most recent year we have covered, 2009, significant new contributions were reported for each of these nine strategies. We have highlighted these at the end of each section. There are four bonds in the five-membered indole ring. In classifying methods for synthesis (Fig. 1), we have focused on the last bond formed. We have also differentiated, in distinguishing Type 1 versus Type 2 and Type 3 versus Type 4, between forming a bond to a functionalized aromatic carbon, and forming a bond to an aromatic carbon occupied only by an H. Type 5 has as the last step C–N bond formation, while with Type 6 the last step is C–C bond formation. In Type 7, the benzene ring has been derived from an existing cyclohexane, and in Type 8, the benzene ring has been built onto an existing pyrrole. Finally, in Type 9, both rings have been constructed. Fig 1 The nine types of indole synthesis. There are several name reactions associated with indole synthesis. We have tried to note these in context, and to group examples of a particular name reaction together. For convenience, the ‘name reaction’ indole syntheses mentioned in this review are: Bartoli indole synthesis—Type 1 Bischler indole synthesis—Type 5 Fischer indole synthesis—Type 1 Hemetsberger indole synthesis—Type 3 Julia indole synthesis—Type 5 Larock indole synthesis—Type 5 Leimgruber–Batcho indole synthesis—Type 5 Madelung indole synthesis—Type 6 Nenitzescu indole synthesis—Type 7 Reissert indole synthesis—Type 5 Sundberg indole synthesis—Type 5 While it might be sufficient to merely label the nine strategies 1–9, for ease of recollection we have also associated each strategy with the name of an early or well-known practitioner. The division of strategies is strictly operational. Thus, the Fischer indole synthesis is classified as Type 1, Ar–H to C2, since that is the way it is carried out, even though the last bond formed, as the reaction proceeds, is in fact N to C1.